dbSNP rs1554122911: TUBB2A:p.Met388Thr (chr6-3154038-A-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_001069.3(TUBB2A):c.1163T>C(p.Met388Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 24)

Consequence

TUBB2A
NM_001069.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 9.12

Publications

0 publications found

Variant links:

Genes affected

TUBB2A (HGNC:12412): (tubulin beta 2A class IIa) Microtubules, key participants in processes such as mitosis and intracellular transport, are composed of heterodimers of alpha- and beta-tubulins. The protein encoded by this gene is a beta-tubulin. Defects in this gene are associated with complex cortical dysplasia with other brain malformations-5. Two transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

TUBB2A Gene-Disease associations (from GenCC):

complex cortical dysplasia with other brain malformations 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
tubulinopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

TUBB2A links:

ENSG00000309609 (HGNC:):

ENSG00000309609 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001069.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the TUBB2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 5.2633 (above the threshold of 3.09). Trascript score misZ: 6.0248 (above the threshold of 3.09). GenCC associations: The gene is linked to complex cortical dysplasia with other brain malformations 5, tubulinopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

PP5

Variant 6-3154038-A-G is Pathogenic according to our data. Variant chr6-3154038-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437124.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001069.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2A	NM_001069.3	MANE Select	c.1163T>C	p.Met388Thr	missense	Exon 4 of 4	NP_001060.1
	TUBB2A	NM_001310315.2		c.908T>C	p.Met303Thr	missense	Exon 4 of 4	NP_001297244.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TUBB2A	ENST00000333628.4	TSL:1 MANE Select	c.1163T>C	p.Met388Thr	missense	Exon 4 of 4	ENSP00000369703.2
TUBB2A	ENST00000940056.1		c.1052T>C	p.Met351Thr	missense	Exon 3 of 3	ENSP00000610115.1
TUBB2A	ENST00000679400.1		n.1219T>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Complex cortical dysplasia with other brain malformations 5 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.64

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.4

PhyloP100

9.1

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.2

REVEL

Pathogenic

0.93

Sift4G

Uncertain

0.035

Polyphen

0.64

Vest4

0.93

MutPred

0.79

Loss of MoRF binding (P = 0.0943)

MVP

0.98

ClinPred

1.0

GERP RS

5.1

Varity_R

0.78

gMVP

1.0

Mutation Taster

=5/95

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over